PROJECT SUMMARY Asthma remains a significant global public health burden. In our previous integrative-metabolomics based R01, R01HL123915, we exceeded our overarching goal of substantially contributing to the understanding of the metabolic dysregulation underlying asthma phenotypes, as evidenced by the publication of 30 peer-reviewed manuscripts, with >20 more in development. We extended well beyond the scope of the initial proposal through (i) generating and analyzing metabolic and multi-omic data in multiple additional cohorts; and (ii) developing a collaborative ?metabolomic epidemiology? research team and forging key cross-disciplinary global collaborations, including access to multiple large prospective cohorts. Together these accomplishments have driven the advancement of Dr. Lasky-Su as a globally recognized leader in this emerging field. In this renewal, we will leverage the powerful combination of our data, experience, expertise, and most importantly the generated scientific hypotheses, specifically as they relate to the role of dysregulated sphingolipid, n-3/n-6 PUFA, and steroid metabolism in asthma. These findings form the basis of the hypotheses and direction of this renewal, in which we hypothesize that metabolic dysregulation associated with asthma-influencing metabolites is partially regulated by interconnected genetic, epigenetic and transcriptomic features that are crucial for optimal understanding of metabolomic endotypes of asthma. In order to test this hypothesis, we propose to (i) conduct the largest metabolomics meta-analysis of asthma phenotypes to date using >50,000 individuals from >30 international cohorts (AIM ONE); (ii) utilize targeted assays to absolutely quantify key asthma-influencing metabolites in three diverse asthma cohorts, identified through our previous work in R01HL123915 and augmented by Aim 1 (AIM TWO). This will enable us to move beyond hypothesis generation to clinical translation, through the generation of metabolomic profiles and clinically informative endotypes (i.e. asthma subtypes defined by their underlying mechanisms). Uniquely, we will integrate five additional omic data types with the targeted metabolites to refine these endotypes and identify the upstream omic drivers underlying the mechanistic differences that distinguish them (AIM THREE). The successful completion of these aims will enable us to achieve the overarching objective of this renewal: to provide the most comprehensive characterization of metabolomic profiles of asthma to date. It will also generate new resources for both the metabolomics and the asthma communities in the forms of large-scale data generation, statistical developments for combining diverse metabolomics studies (via COMETS-Analytics), and by addressing questions of heterogeneity across metabolomics studies. This renewal will expand and build upon the considerable success of R01HL123915, enabling clinical translatability, and the formulation of knowledge with power to transform the current landscape of asthma metabolomics.